Editor's Comment: In this study, a subset of CFS patients was found to have an immune deficiency that allows Epstein-Barr virus (EBV) to replicate, even beyond the acute stage of the original infection. B-cells are the part of the immune system that "remembers" pathogens (viruses, bacteria, etc.) in order to mount attacks against future infections. The patients in this study showed an impaired B- and T-cell response to EBV, leading to latent virus reactivation. (EBV, like all herpesviruses, remains in the body forever.) The early theory that CFS was a form of "chronic mono" now appears to have substantiation.

By Madlen Loebel et al.

Abstract

Epstein-Barr virus (EBV) has long been discussed as a possible cause or trigger of Chronic Fatigue Syndrome (CFS). In a subset of patients the disease starts with infectious mononucleosis and both enhanced and diminished EBV-specific antibody titers have been reported.

In this study, we comprehensively analyzed the EBV-specific memory B- and T-cell response in patients with CFS. While we observed no difference in viral capsid antigen (VCA)-IgG antibodies, EBV nuclear antigen (EBNA)-IgG titers were low or absent in 10% of CFS patients. Remarkably, when analyzing the EBV-specific memory B-cell reservoir in vitro a diminished or absent number of EBNA-1- and VCA-antibody secreting cells was found in up to 76% of patients. Moreover, the ex vivo EBV-induced secretion of TNF-alpha and IFN-gamma was significantly lower in patients.

Multicolor flow cytometry revealed that the frequencies of EBNA-1-specific triple TNF-alpha/IFN-gamma/IL-2 producing CD4+ and CD8+ T-cell subsets were significantly diminished whereas no difference could be detected for HCMV-specific T-cell responses. When comparing EBV load in blood immune cells, we found more frequently EBER-DNA but not BZLF-1 RNA in CFS patients compared to healthy controls suggesting more frequent latent replication.

Taken together, our findings give evidence for a deficient EBV-specific B- and T-cell memory response in CFS patients and suggest an impaired ability to control early steps of EBV reactivation. In addition the diminished EBV response might be suitable to develop diagnostic marker in CFS.